Biomedical subjects

M E Kelly

Publications and source records attributed to M E Kelly.

At least 73 records · Page 4Linked to original sources

PubMed1992

The interaction of R(+)- and S(-)-zacopride with PCPA to modify rodent aversive behaviour.

The interaction of R(+)- and S(-)zacopride (0.00001-10 mg/kg i.p.) with parachlorophenylalanine (PCPA, 3 day treatment 100 mg/kg i.p.) to modify behaviour in an aversive situation was investigated in the mouse black and white test box and rat social interaction test. R(+)-Zacopride (but not S(-)zacopride) and PCPA had an anxiolytic profile of action to reduce aversive responding in both species. Their established anxiolytic profiles were abolished by a subsequent treatment with S(-)zacopride. In contrast, S(-)-zacopride was less or ineffective if administered simultaneously with R(+)-zacopride. A co-treatment of PCPA with R(+)-zacopride also inhibited the anxiolytic profiles observed to the individual treatments. It is concluded that there is a complex interaction between the isomers of zacopride to modify responding to an aversive situation that is dependent on the temporal sequence of drug administration, and which may be modified by changes in basal 5-hydroxytryptamine (5-HT) tone and agonist, partial agonist and antagonist effects at the 5-HT3 receptor.

Animals↗

PubMed1992

Profiles of interaction of R(+)/S(-)-zacopride and anxiolytic agents in a mouse model.

The mouse black and white test box was used to measure changes in behaviour in an aversive situation where the administration of R(+)-zacopride (but not S(-)-zacopride) alone decreased aversive responding to the white area. A similar anxiolytic profile of action was observed using parachlorophenylalanine (PCPA), whose effects were antagonised by a co-treatment with R(+)-zacopride and reversed by S(-)-zacopride to an exacerbation of the aversive response. An anxiolytic profile of action was also observed using ondansetron, granisetron, chlordiazepoxide, diazepam, ritanserin, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), E4424 (2-[4-[4-(4-chloro-l-pyrazoyl)butyl]-l-piperazinyl]-pyrimidine), umepsirone, DuP753 (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[2(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)]-imidazole), SQ29,852 ((S)-1-[6-amino-2[hydroxy)(4-phenyl-butyl)phosphinyl]-oxy)-1- nexy]-2-proline), devazepide and guanfacine, and this was retained following co-treatment with PCPA. The anxiolytic profile of action of PCPA was also retained following co-treatment with renzapride which when administered alone failed to modify behaviour. However, the ability of chlordiazepoxide, diazepam, ondansetron and E4424 (but not devazepide, DuP753 or SQ29,852) to reduce aversive responding was inhibited by co-treatment with R(+) and/or S(-)-zacopride. It is concluded that the reduction in aversive responding caused by pharmacological manipulation at the benzodiazepine, 5-HT receptor subtypes 5-HT1A, 5-HT1C/5-HT2 and 5-HT3 (but not at the cholecystokin CCKA or angiotensin receptors or inhibition of angiotensin converting enzyme) can be inhibited by R(+) and S(-)-zacopride. The data is discussed in terms of zacopride having an agonist or partial agonist effect at the 5-HT3 receptor.

Animals↗

PubMed1992

Inwardly rectifying potassium current in rabbit osteoclasts: a whole-cell and single-channel study.

Ionic conductances of rabbit osteoclasts were investigated using both whole-cell and cell-attached configurations of the patch-clamp recording technique. The predominant conductance found in these cells was an inwardly rectifying K+ conductance. Whole-cell currents showed an N-shaped current-voltage (I-V) relation with inward current activated at potentials negative to EK. When external K+ was varied, I-V curves shifted 53 mV/10-fold change in [K+]out, as predicted for a K(+)-selective channel. Inward current was blocked by Ba2+ and showed a time-dependent decline at negative potentials, which was reduced in Na(+)-free external solution. Inward single-channel currents were recorded in the cell-attached configuration. Single-channel currents were identified as inward-rectifier K+ channels based on the following observations: (i) Unitary I-V relations rectified, with only inward current resolved. (ii) Unitary conductance (gamma) was 31 pS when recorded in the cell-attached configuration with 140 mM K+ in the pipette and was found to be dependent on [K+]. (iii) Addition of Ba2+ to the pipette solution abolished single-channel events. We conclude that rabbit osteoclasts possess inwardly rectifying K+ channels which give rise to the inward current recorded at negative potentials in the whole-cell configuration. This inwardly rectifying K+ current may be responsible for setting the resting membrane potential and for dissipating electrical potential differences which arise from electrogenic transport of protons across the osteoclast ruffled border.

Animals↗

PubMed1992

Anxiolytic-like actions of anpirtoline in a mouse light-dark aversion paradigm.

The anxiolytic-like potential of anpirtoline was assessed in a mouse light/dark aversion test. Anpirtoline (1.0 ng kg(-1)-1.0 micrograms kg-1 i.p.) reduced the aversive responding of mice. This was detected as an increase in the latency to locate the non-aversive compartment and by decreases in the percentage of the time spent in the dark compartment, and the numbers of rears and line crossings in the dark compartment. In radioligand binding studies anpirtoline displayed submicromolar affinity for 5-HT1A, 5-HT1B and 5-HT3 receptor recognition sites (Ki = 151, 28 and 30 nM, respectively) and more modest affinity for 5-HT2 receptor recognition sites (Ki = 1.48 microM). It is concluded that anpirtoline has a unique spectrum of affinity for 5-HT receptor subtypes, its interaction with which may account for its anxiolytic-like activity.

Animals↗

PubMed1992

Angiotensin-converting enzyme inhibition, angiotensin, and cognition.

In these studies, we have investigated possible cognition-enhancing effects of angiotensin-converting enzyme (ACE) inhibition, and putative neurochemical correlates for these actions. In a mouse habituation model, ACE inhibitors improved basal performance and antagonized scopolamine-induced deficits. The performance of aged mice and those with lesions of the nucleus basalis was also improved. ACE inhibition also improved scopolamine-impaired performance of rats in a swim-maze model. Neurochemical studies showed that a low dose (10 micrograms/kg i.p.) of ceranapril caused significant alterations in ex vivo rat brain catecholamine levels in the nucleus accumbens, amygdala, and septum. In further studies, angiotensin II (Ang II) was shown to decrease potassium-stimulated [3H] acetylcholine release from slices of rat entorhinal and human temporal cortex, an effect that could be antagonized by the angiotensin receptor antagonist [1-sar,8-thr]Ang II. It is concluded that ACE inhibition can improve both basal and impaired performance in animal models of learning, and that this improvement may be in part a consequence of the removal by ACE inhibition of an inhibitory tone on central acetylcholine release, and/or an effect on central catecholaminergic function.

Acetylcholine↗

PubMed1992

Profile of action of a novel 5-hydroxytryptamine1A receptor ligand E-4424 to inhibit aversive behavior in the mouse, rat and marmoset.

E-4424 (2-(4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl)pyrimidine) was shown to be a 5-hydroxytryptamine1A receptor ligand in radioligand binding assays and in an in vitro guinea pig ileum preparation had both 5-hydroxytryptamine1A antagonist and agonist effects. The antagonist/agonist ratio of E-4424 was greater than in the case of buspirone and ipsapirone. E-4424 was compared to diazepam, buspirone and ipsapirone to inhibit the behavioral response to an aversive situation in the mouse black and white test box, the rat social interaction test and a marmoset human threat test. The acute administration of E-4424 (0.0001-0.5 mg/kg, i.p.) to the mouse decreased aversion to the white area of the test box and was as effective as diazepam (0.125-1.0 mg/kg, i.p.) and much more potent than buspirone (0.25-1.0 mg/kg, i.p.) or ipsapirone (0.5-5.0 mg/kg, i.p.). E-4424 was also effective in enhancing rat social interaction and reducing anxiety-related behaviors in the marmoset and was again more potent than diazepam, buspirone or ipsapirone. Withdrawal from a 14-day administration of diazepam, cocaine, nicotine or alcohol exacerbated the response to the aversive situation in the mouse test. This was not observed after withdrawal from a chronic treatment with E-4424, buspirone or ipsapirone. However, E-4424 administered during drug withdrawal prevented the response caused by withdrawal from cocaine, alcohol, nicotine and diazepam: buspirone was ineffective and ipsapirone only attenuated that syndrome after alcohol withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Suppression of amygdala kindling with massed stimulation: effect of noradrenaline antagonists.

Afterdischarge (AD) triggered by brief, daily stimulation of the amygdala progressively increases in complexity and duration and, over days, develops into generalized convulsions. This progression, called kindling, is delayed by noradrenaline (NA). When brief stimulation of the amygdala occurs too frequently (massed), there is a suppression of AD growth and little evidence of kindling. Previously we showed that depletion of NA before massed amygdala stimulation prevented the suppression of AD growth described above, and readily precipitated generalized seizures. In the present report, we examined the role of NA in maintaining this suppression of AD growth, after it was well established. We showed that suppression of AD development during the first 15 massed stimulations (interstimulus interval of 5 min) was reduced by subsequent injection of the NA alpha 2 antagonist, yohimbine, with most rats exhibiting occasional generalized convulsions. Conversely, rats exposed to the beta antagonist, propranolol, like controls, not only showed suppressed AD growth, but also elevated AD thresholds. Three weeks later, only a small positive transfer to daily kindling was observed in all groups. We conclude that alpha 2 NA receptors help maintain suppression of AD growth induced by massed stimulation of the amygdala, while beta receptors provide only a small proepileptic influence. These results and those from the 'rapid' kindling model (Lothman et al., Brain Research, 360 (1985) 83-91) are compared, and related to NA receptor subtype variations in the amygdala and hippocampus.

Amygdala↗

PubMed1991

K+ and Cl- currents in freshly isolated rat osteoclasts.

Membrane electrical properties of freshly isolated rat osteoclasts were studied using patch-clamp recording methods. Characterization of the passive membrane properties indicated that the osteoclast cell membrane behaved as an isopotential surface. The specific membrane capacitance was 1.2 +/- 0.3 microF/cm2 (mean +/- SD), with no difference between cells plated on glass and those adhering to a permeable collagen substrate. The current/voltage (I/V) relationship of all cells showed inward rectification and I/V curves shifted 51 mV positive per tenfold increase of [K+]out, indicating an inwardly rectifying K+ conductance. The voltage dependence of the K+ chord conductance (gK) also shifted positive along the voltage axis, and the maximum conductance increased, with elevation of [K+]out. gK for cells bathed in 4.7 mM [K+]out increased e-fold per 12 mV hyperpolarization, and half-maximal activation was at -89 mV. Approximately 18% (50 pS/pF) of the maximum gK was active at -70 mV. Inward single-channel currents were recorded in cell-attached patches at hyperpolarizing potentials. With symmetrical K+, channel conductance was 25 +/- 3 pS and reversal was close to the K+ equilibrium potential, consistent with this K+ channel underlying the whole-cell K+ currents. With both conventional whole-cell and perforated-patch recording, no voltage-activated Ca2+ current was detected. In approximately 30% of osteoclasts studied, an outwardly rectifying current was observed, which was reversibly blocked by 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS) and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid (SITS). This DIDS- and SITS-sensitive current reversed direction at the chloride equilibrium potential. We conclude that an inwardly rectifying K+ current is present in all rat osteoclasts and that some osteoclasts also exhibit an outwardly rectifying Cl- current. Both these membrane conductances may play an important physiological role by dissipating the potential that arises from the electrogenic transport of H+ across the ruffled membrane of the osteoclast.

Animals↗

PubMed1991

The effects of umespirone as a potential anxiolytic and antipsychotic agent.

Umespirone was compared to buspirone, diazepam and clozapine as a potential anxiolytic and antipsychotic agent. In the mouse black and white test box, umespirone was considerably more potent than diazepam or buspirone to reduce aversive responding, tolerance to its effects was not observed and sedation was absent, a chronic treatment and withdrawal was not associated with an anxiogenic profile, and umespirone prevented the behavioural consequences of withdrawal from diazepam. Umespirone also had an anxiolytic profile of action in the tests of rat social interaction and in the marmoset exposed to a human threat. Both umespirone and clozapine reduced the hyperactivity induced by the infusion of dopamine into the nucleus accumbens of rat. In radioligand binding assays umespirone demonstrated nanomolar affinity for the alpha 1-adrenoceptor and the 5-HT1A and dopamine D2 receptors. It is concluded that umespirone may present as a novel psychotropic agent with anxiolytic and antipsychotic potential.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist.

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1991

Anxiolytic effects of CCK-B antagonists.

PD134308 and PD135158 are highly selective CCK-B receptor antagonists and were used to investigate the role of CCK-B receptors in aversive responding in rodent and primate models of anxiety. Both PD134308 and PD135158 were as effective as diazepam to antagonise aversive behaviour in the mouse light/dark discrimination test, in the rat social interaction and elevated X-maze tests, and in a marmoset 'human threat' model. However, the CCK-B antagonists were much more potent than diazepam and their effects were recorded over an extensive dose range. Furthermore, even at high doses, sedation or muscle relaxation was not observed and anxiogenesis was absent after withdrawal from a subchronic treatment. In contrast, withdrawal from drugs of abuse, diazepam, alcohol, cocaine and nicotine was associated with a withdrawal anxiogenesis that was completely prevented by PD134308 and PD135158. It is concluded that CCK-B receptors are involved in aversive-anxiety responding and that CCK-B receptor antagonists may provide a novel and improved approach to the treatment of anxiety and withdrawal from drugs of abuse.

Animals↗

PubMed1991

Cognitive enhancing actions of PD123177 detected in a mouse habituation paradigm.

The anxiolytic-like and cognitive enhancing potential of PD123177, a non-peptide with selectivity for the angiotensin II-2 receptor recognition site, was assessed in a mouse light/dark aversion test and habituation test, respectively. PD123177 (0.01 ng kg-1 to 1.0 mg kg-1 i.p.) failed to alter the behavioural repertoire of animals in the light/dark aversion test. In contrast, daily administration of PD123177 (10.0 ng kg-1 i.p. b.d.) enhanced the performance of mice in a habituation test. In addition, PD123177 overcame the cognitive impairment induced by the administration of scopolamine (0.25 mg kg-1 i.p.). Such findings indicate for the first time a functional role for the angiotension II-2 receptor and further implicate the angiotensin system in the modulation of cognitive processes.

Angiotensin II↗

PubMed1991

Atropine occlusion in the treatment of strabismic amblyopia and its effect upon the non-amblyopic eye.

A total of 189 cases with amblyopia, where atropine sulphate 1% had been used as a method fo unilateral occlusion, were reviewed. The results show that after atropine had been appropriately applied, permanent reversal of amblyopia is rare, and unwanted side-effects are few and of minor nature. Pupil size, light reflex and accommodation of the atropinized eye appear to be unaffected. The angle of squint was unaffected and fixation of the amblyopic eye either remained unchanged or shifted to a more central point.

Amblyopia↗

PubMed1990

The effect of ketotifen in rodent models of anxiety and on the behavioural consequences of withdrawing from treatment with drugs of abuse.

Ketotifen was compared to diazepam to inhibit aversive responding of the mouse in a black and white test box and in the rat social interaction test. Both drugs reduced aversive responding in the mouse to the brightly illuminated area of the test box and facilitated social interaction in the rat; ketotifen was approximately 100 times more potent than diazepam. The chronic administration of diazepam, ethanol, nicotine and cocaine in the mouse also reduced aversive responding but their withdrawal was associated with an increased behavioural suppression. The administration of ketotifen during the period of withdrawal from diazepam, ethanol, nicotine and cocaine prevented the exacerbation in aversive responding. It is concluded that ketotifen, like diazepam and 5-HT3 receptor antagonists, can reduce behavioural suppression in rodent models of anxiety and attenuate the behavioural consequences of withdrawal from treatment with drugs of abuse.

Animals↗

PubMed1990

Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset.

The abilities of the ACE inhibitors captopril and SQ29,852 to modify aversive behaviour was compared to the effects of diazepam in the light/dark exploration test in the mouse, the elevated plus maze and social interaction test in the rat, and in anxiety-related behaviours induced by human threat in the marmoset. In the four tests the acute administration of captopril, SQ29,852 and diazepam had the same profiles of action to reduce aversive responding. This was also observed during chronic administration with the three agents in the mouse. However, withdrawal from a chronic treatment with diazepam precipitated a syndrome of increased aversion, whereas withdrawal from treatment with captopril and SQ29,852 was uneventful, values waning to control levels. Withdrawal from treatment with ethanol, nicotine and cocaine also enhanced aversive responding. Treatment with captopril and SQ29,852 antagonised the behavioural consequences of withdrawal from treatment with diazepam and nicotine and SQ29,852 also blocked the consequences of withdrawal from ethanol and cocaine. It is concluded that captopril and SQ29,852 have an anxiolytic profile of action in 3 species, that cessation of treatment is not associated with a withdrawal syndrome, that the ACE inhibitors cross tolerate with diazepam and can antagonise the behavioural consequences of withdrawal from treatment with drugs of abuse.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Sites of action of ondansetron to inhibit withdrawal from drugs of abuse.

The cerebral site of action of the selective 5-HT3 receptor antagonist ondansetron to influence the behavioural consequences of withdrawal from subchronic treatment with diazepam, ethanol, nicotine or cocaine was studied in the light/dark exploration test in the mouse. The aversive response to the light compartment of the test box was reduced during a subchronic treatment with peripherally administered diazepam, ethanol, nicotine and cocaine, but was exacerbated following withdrawal from the 4 treatments. The behavioural consequences of withdrawal from diazepam (10 mg/kg IP b.i.d. 14 days), ethanol (8%/w/v drinking water for 14 days), nicotine (0.1 mg/kg IP b.i.d. 14 days) or cocaine (1.0 mg/kg IP b.i.d. 14 days) were antagonised by ondansetron injected into the amygdala and dorsal raphe nucleus (1-10 ng); injections of ondansetron (10 ng) into the median raphe nucleus, the nucleus accumbens and striatum were ineffective. It is concluded that the amygdala and dorsal raphe nucleus may be sites of action for ondansetron to antagonise the aversive behaviour caused by withdrawal from 4 common drugs of abuse in a mouse model, and that 5-HT projections from the dorsal raphe nucleus may be involved in aversive behaviour.

Amygdala↗

PubMed1990

Actions of ORG 5222 as a novel psychotropic agent.

ORG 5222 is a tetracyclic compound with high affinity for dopamine and 5-HT2 receptors. ORG 5222 was compared to fluphenazine in behavioural tests and was shown to be less potent to cause catalepsy on peripheral administration or to induce asymmetric body posturing following intrastriatal injection. On injection into the nucleus accumbens, ORG 5222 antagonised spontaneous and amphetamine-induced hyperactivity. The peripheral administration of ORG 5222 antagonised the hyperactivity induced by infusion of dopamine into the nucleus accumbens of rat or ventral striatum of the marmoset and, unlike the use of fluphenazine, there was no evidence of a 'rebound' hyperactivity after discontinuation of treatment. Furthermore, ORG 5222 prevented changes in responsiveness to dopamine agonist challenge following dopamine infusion. In a mouse black and white test box and the rat elevated plus maze ORG 5222 released exploratory behaviour suppressed by the aversive white or elevated environments. It is concluded that ORG 5222 is effective to antagonise mesolimbic dopamine function in the rodent and primate and an aversive behaviour in rodent tests. Such effects reveal a novel profile of action of ORG 5222 in behavioural paradigms predictive of antipsychotic and anxiolytic potential and may relate to a dopamine and 5-HT receptor antagonism.

Amphetamines↗

PubMed1990

The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates.

The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. Arecoline failed to improve basal performance in young adult mice but inhibited the impairment caused by scopolamine and lesions of the nucleus basalis magnocellularis. In the T-maze reinforced alternation task in rats, ondansetron and arecoline antagonised a scopolamine-induced impairment. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.

Aging↗